Mononuclear cell composition and activation in blood and mucosal tissue of eosinophilic esophagitis

IntroductionEosinophilic esophagitis (EoE) is a chronic, inflammatory, antigen-driven disease of the esophagus. Tissue EoE pathology has previously been extensively characterized by novel transcriptomics and proteomic platforms, however the majority of surface marker determination and screening has been performed in blood due to mucosal tissue size limitations. While eosinophils, CD4+ T cells, mast cells and natural killer (NK) T cells were previously investigated in the context of EoE, an accurate picture of the composition of peripheral blood mononuclear cells (PBMC) and their activation is missing.MethodsIn this study, we aimed to comprehensively analyze the composition of peripheral blood mononuclear cells and their activation using surface marker measurements with multicolor flow cytometry simultaneously in both blood and mucosal tissue of patients with active EoE, inactive EoE, patients with gastroesophageal reflux disease (GERD) and controls. Moreover, we set out to validate our data in co-cultures of PBMC with human primary esophageal epithelial cells and in a novel inducible mouse model of eosinophilic esophagitis, characterized by extensive IL-33 secretion in the esophagus.ResultsOur results indicate that specific PBMC populations are enriched, and that they alter their surface expression of activation markers in mucosal tissue of active EoE. In particular, we observed upregulation of the immunomodulatory molecule CD38 on CD4+ T cells and on myeloid cells in biopsies of active EoE. Moreover, we observed significant upregulation of PD-1 on CD4+ and myeloid cells, which was even more prominent after corticosteroid treatment. With co-culture experiments we could demonstrate that direct cell contact is needed for PD-1 upregulation on CD4+ T cells. Finally, we validated our findings of PD-1 and CD38 upregulation in an inducible mouse model of EoE.DiscussionHerein we show significant alterations in the PBMC activation profile of patients with active EoE in comparison to inactive EoE, GERD and controls, which could have potential implications for treatment. To our knowledge, this study is the first of its kind expanding the multi-color flow cytometry approach in different patient groups using in vitro and in vivo translational models

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials

Tumor microenvironment-derived monoacylglycerol lipase provokes tumor-specific immune responses and lipid profiles

We recently described that monoacylglycerol lipase (MGL) is present in the tumor microenvironment (TME), increasing tumor growth. In this study we compare the implications of MGL deficiency in the TME in different tumor types. We show that subcutaneous injection of KP (KrasLSL-G12D/p53fl/fl, mouse lung adenocarcinoma) or B16-F10 cells (mouse melanoma) induced tumor growth in MGL wild type (WT) and knockout (KO) mice. MGL deficiency in the TME attenuated the growth of KP cell tumors whereas tumors from B16-F10 cells increased in size. Opposite immune cell profiles were detected between the two tumor types in MGL KO mice. In line with their anti-tumorigenic function, the number of CD8+ effector T cells and eosinophils increased in KP cell tumors of MGL KO vs. WT mice whereas their presence was reduced in B16-F10 cell tumors of MGL KO mice. Differences were seen in lipid profiles between the investigated tumor types. 2-arachidonoylglycerol (2-AG) content significantly increased in KP, but not B16-F10 cell tumors of MGL KO vs. WT mice while other endocannabinoid-related lipids remained unchanged. However, profiles of phospho- and lysophospholipids, sphingomyelins and fatty acids in KP cell tumors were clearly distinct to those measured in B16-F10 cell tumors. Our data indicate that TME-localized MGL impacts tumor growth, as well as levels of 2-AG and other lipids in a tumor specific manner

FReDA – The German Family Demography Panel Study

The study programme “FReDA – The German Family Demography Panel” is a cooperative project of the German Federal Institute for Population Research, GESIS – Leibniz Institute for the Social Sciences, and – as representatives of the pairfam consortium – the University of Cologne and the Friedrich Schiller University Jena. FReDA is a longitudinal study on family and demography with an international perspective and a dyadic multi-actor design. As part of the international Generations and Gender Programme (GGP), the FReDA-GGS sample allows for comparisons with several other European countries. From wave 2 onwards, the pairfam sample, which was first recruited in 2008, will be integrated into the FReDA panel as the FReDA-pairfam sample and will be followed with a joint FReDA survey instrument. FReDA focuses thematically on family life and intimate relationships. The questionnaires for the first wave of FReDA have a modular design and comprise the following main topics: • Demography • Health, well-being, and personality • Work and income • Family planning and fertility • Couples’ relationships and partnerships • Parent–child and intergenerational relationships • Attitudes and values • COVID-19 pandemic For the recruitment of the FReDA-GGS sample, a probability-based sample of 108,256 anchor persons aged between 18 and 49 years and resident in Germany was drawn from the population registers of municipalities in Germany. The first FReDA wave, W1, was conducted in multiple subwaves consisting of the recruitment wave W1R and the two subwaves W1A and W1B. The interviews were conducted in a self-administered web-based (CAWI) or paper-based (PAPI) mode by the infas Institute for Applied Social Science. Data for the first FReDA wave were collected from April to June 2021 (W1R), July to September 2021 (W1A), and November 2021 to January 2022 (W1B). Additionally, data on anchor persons’ partners were collected from August to November 2021 (W1Apartner). A comprehensive overview of the methodological and conceptual principles of the FReDA study is provided in the FReDA reference paper by Schneider et al. (2021) .Recruitment subwave W1R: Value orientation and attitudes: traditional marriage concept (Unmarried cohabitation is permissible, marriage for life, divorce is permissible); traditional family (women need children to be fulfilled, men need children to be fulfilled, homosexual couple rights); gender role (pre-school child suffers if mother works, working mother can establish warm and secure relationship with child, women should care for family and less for career); intergenerational care values (parents provide financial help, children should care for parents, children should provide financial help for parents); gender values (better political leaders, for whom is a university education most important, for whom is having a job more important, for whom is housework and looking after children more important, better at caring for children). Corona: experience during the COVID-19 pandemic (personally heavily burdened, fear of falling ill, can also see the positive side, financial losses, difficulty restricting personal contact); assessment of political measures to fight the Corona virus (too much, just enough, too little). Demography: sex; sex according to register data; age; date of birth (month, year); current marital status; respondent has a partner; respondent has a partner for at least three months, living with partner; place first met current partner; satisfaction with the current romantic relationship; no children; number of biological children with current partner and with former partner; number of adopted children and of stepchildren; household size; highest school-leaving certificate; highest vocational qualification; years of education; education (ISCED-11); current situation; satisfaction with the actual employment situation; date school-leaving certificate reached (month, year); type of academic institution; date vocational education reached (month, year); degree of urbanization; currently living in eastern Germany; place of birth (federal state); country of birth; citizenships; language spoken at home; migration background: born in Germany; German citizenship; additional citizenship; date of immigration (month, year); financial situation of household (subjective); total household net income (last month, categories); internet connection; frequency of internet use; satisfaction with life as a whole. Additionally coded: respondent ID (anchor); subwave; sample (FReDA-GGS); interview date (day, month, year); mode; device used by respondent; total duration of web interview in seconds; contact strategy; number of mailings; interview assessment (the questionnaire was interesting, varied, important for research, long, difficult, too personal); panel consent; Flag variables: inconsistency with register data; partial interviews; unusually short interview duration; weight: design weight; design weight scaled to net sample size; start of survey field period; end of survey field period. Paradata: respondent ID (anchor); subwave; time and date of first access to questionnaire (absolute cumulated duration); time and date of last access to questionnaire (absolute cumulated duration); viewport width first page (in pixels); viewport height first page (in pixels); viewport width last page (in pixels); viewport height last page (in pixels); last page processed in questionnaire; number of interruptions; absolute cumulated duration for pages (milliseconds); soft prompt for page consent. Wave W1A: Employment: employment status; paid employment in the last week, full-time/part-time employment; hours worked per week, commuting between home and work (duration in hours and minutes); perceived stress during the last three months (too tired to do housework, difficulty meeting family obligations, too tired at work, difficulty concentrating because of family obligations, private conflicts affect performance); current situation; continuing education measures in the last twelve months. Information on children, ex-partners, and household members of the anchor in repeat loops. For respondents in paper-based mode, the number of loop variables is limited to four children, four ex-partners, and four household members. For respondents in web-based mode, the maximum number of blocks of loop variables is higher. Partner and partnership information: partner´s education: highest general education degree, highest vocational education degree, years of education; ISCED 2011; type of college/institution; current situation; paid job in the last week; hours worked per week; health restrictions in the last six months; country of birth; citizenships; country of birth Germany; German citizenship; other citizenship; federal state at birth; moved to Germany (month and year); duration of current partnership/ marriage in months; date of beginning relationship with current partner (month, year); married to current partner; date of marriage (month, year); registered civil partnership with current partner; date of registration of civil partnership (month, year); ever married to current partner(s); date of divorce from current partner (month, year); date of moving in with current partner (month, year), choice or circumstances of living apart; reason for living apart (anchor and partner; circumstances of living apart; distance from current partner´s home (duration in hours and minutes); number of days of face-to-face meetings and contacts with current partner(s) per week, month, or year; Intention to move in together in the next three years; intention to marry; intention to move in together and marry; frequency of disagreements about housework, money, leisure activities, relationship with friends, with parents, family planning, and child rearing issues; behavior in case of serious disagreements; serious thoughts about separation or divorce. Information on previous partnerships: Previous partnerships of at least three months duration; number of previous partnerships; number of cohabitations or marriages in previous partnerships; sex and age (date of birth month, year) of ex-partner; way of getting to know ex-partner; date of beginning of relationship (month, year); date of moving in together (month, year); married to ex-partner; date of marriage (month, year); type of end partnership (separation/death of partner); divorce from ex-partner), date of divorce (month, year); partner who filed for divorce. Information on children: child living, status of child; other natural parent of child; sex of child; date of birth (month year); date of death (month, year); child lives in same household; place of residence of child if not in same household; number of days per week, month, or year with care of child; number of overnights of child per week in respondent´s household; current situation; health limitations; general health; child has ever lived in the same household for more than three months; number of days per week, month, or year with face-to-face meetings with child; number of days per week, month, or year with other contact with child; distance to child´s other residence (duration in hours and minutes); satisfaction with relationship with child. Natural children with ex-partner; number of natural children with respective former partner; stepchildren with ex-partner; number of stepchildren with respective former partner; natural children of ex-partner; number of natural children with respective former partner; children with someone else; number of children with someone else. Pregnancies and family planning: current pregnancy of respondent or partner; other woman pregnant by respondent; expected date of birth (month, year); pregnancy with youngest child was planned; timing of pregnancy earlier/later than planned or just right; previous pregnancy was planned; timing of previous pregnancy earlier/later than planned or just right; problems getting pregnant for at least twelve months; purely physically able to have a child or to to conceive (anchor and partner); unable to have a child due to sterilization or surgery; diagnosis for infertility or not seen a doctor; time of attempt to become pregnant (month and year); type of fertility treatment; type of contraceptive methods used; sexual intercourse in the last four weeks; desire to have children in the next three years; general desire to have children; intended number of children; ideal number of children for respondent and in general; desired sex of first or next child; age at first menstruation or age at voice change; age at first sexual intercourse. Housing situation: number of rooms in the apartment or house; living space (in square meters); date of moving in (month and year); owner or tenant of the apartment or house; monthly cold rent (in euros); monthly incidental rental costs (in euros); satisfaction with the apartment or house; place of residence three years ago; reason for moving; intended move within Germany; intended move to another country. Household composition: other household members; number of other persons in the household; for the other household members was asked: relationship to this household member; sex; date of birth (month and year); current situation; satisfaction with the relationship to this person; health restrictions of this person in the last six months. Division of household chores between partners; satisfaction with division of chores; assessment of fairness of division of household chores; division of childcare chores; satisfaction with division of childcare chores; household decision-maker about routine household purchases, major household purchases, amount of time spent in own employment, and amount of time spent in partner´s employment; Organization of household income and expenses; length of time receiving Parental Benefit or Parental BenefitPlus for youngest child (in months, anchor, and partner); received regular child care assistance from acquaintances, friends, or relatives in the last 12 months; person providing child care assistance; number of days of child care assistance; payment of one of these persons; regular child care assistance from paid providers (e.g. B. child day care providers); type of child care services used; number of days per week, month, or year; monthly cost of child care; chore assistance from public or private providers; number of days per week, month, or year chore assistance is used; cost per week, month, or year of chore assistance; life satisfaction; self-assessment of health status; frequency of depression tendencies in the last week; net household income (in euros and categorized); assessment of the household´s financial situation; receipt of alimony in the last twelve months from a former partner; payment of alimony in the last twelve months to a former partner. Demography: sex; sex according to registry data; age; date of birth (month, year); age according to registry data; currently residing in East Germany; degree of urbanization; current marital status; current partnership status: same-sex partnership; current partnership status: relationship present; partnership for at least three months; living with partner; how did you meet current partner; satisfaction with current relationship; age and sex of partner; date of birth (month and year) of partner; number of all children, number of biological children, adopted children, and stepchildren born before the interview; number of all children still living, number of all children in the anchor´s household; age of youngest child, number of biological children, and number of adopted children with current partner; children of current partner with someone else and number of these children. Additionally coded were: ID anchor; wave data collection; identifier for sample membership; interview date (day, month, year); participation mode; terminal device; total duration of web interview in seconds; contact strategy; number of mailings; net equivalent income (GCEE); interview rating; consent to panel participation current partner; flag variables: Deviations from registry data, incomplete interviews, strikingly short interview duration, deviations from previous wave, missing information on children with (ex)partners, missing information on children (child loop); weighting factors; field start, field end. Wave W1B: Parents, origin, and childhood: birth mother still living, birth mother living in same household; birth father still living; birth father living in same household; distance to mother´s/father´s residence in hours and minutes; number of days of face-to-face meetings and contacts with mother and father per week, month, or year; satisfaction with relationship with birth mother/father; attachment to birth mother/father; asked for both parents: Age; country of birth; date of birth (month, year); date of death (month, year); country of birth Germany; federal state at birth; birth parents living in a common household; living with birth mother/father in a common household; ever lived apart from birth parents for at least 3 months; date of first separation from parents (month and year); intended change in living situation due to separation from parents in the next three years; parents were married; date of marriage (month and year); separation of parents; date of separation (month and year); siblings: Number of brothers and sisters; number of older siblings; year of birth of first child of birth mother and birth father; childhood in Germany; childhood abroad; federal state during childhood; lived with birth parents during childhood; lived with whom during childhood; quality of relationship between birth parents during childhood; ever lived abroad for more than three months during childhood; occupation (ISCO88) and occupational status of birth mother or of birth father at age 15; years of education of birth parents; highest general education degree (ISCED-11), highest vocational education degree; number of grandparents still living; number of birth children, adopted children, stepchildren, and foster children; grandchildren; number of grandchildren; date of birth of oldest grandchild (month and year). General well-being and health status: life satisfaction; regular need for care; type of health impairments or no diagnosis of health impairments; degree of limitations in activities of daily living in the last six months; limitations since when; infection with Corona virus since the beginning of the pandemic; body weight in kilograms; height in centimeters; happiness scale; loneliness (can rely on people for help with problems, feel general emptiness, miss people around me, can rely on many people, often feel rejected, feel close to people); contacts for important personal matters. Employment situation: current situation; satisfaction with employment status; date of beginning of current situation (month and year); paid employment in the last week; date of beginning of paid employment (month and year); employment full-time or part-time; hours worked per week; commuting between home and work (duration in hours and minutes); arrangement of work hours; flexibility in arrangement of work hours; frequency of working from home per week; frequency of working evenings or nights for at least two hours; workplace evenings or nights at home or elsewhere); frequency of working weekends; workplace weekends at home or elsewhere; probability of job loss; type of organization of current business (private or public); type of current employment contract; flexible work arrangements by employer; additional employment or business; hours worked per week for the additional employment; possible to return to work after maternity or parental leave; intention to return to work after end of maternity or parental leave; intention to take a job or start a business within the next three years; job or business immediately before current situation; previous job situation; previous job position; previous number of supervised employees; reason for leaving previous job; current or most recent occupation (ISCO-08); current or most recent occupational position. Partnership: steady relationship; date of birth of partner; relationship existed at the time of last interview; satisfaction with partner relationship; information on partner´s current employment and daily activities: Current situation; paid job in the last week; reason for leaving previous job; current job (ISCO-88); job position; number of supervised employees; hours worked per week; work schedule arrangement; frequency of working from home per week; frequency of working in the evening or at night for at least two hours; workplace at home or elsewhere in the evening or at night); frequency of working on weekends; working weekends at home or elsewhere; likelihood of job loss; organizational form of current business (private or public); type of current employment contract; flexible work arrangements by employer; additional employment or business; hours worked per week for the additional employment. Financial situation of the household: estimated current market value of owned real estate and land; real estate loan; outstanding amount for this loan; amount of the household´s monthly payments for real estate loans; subjective assessment of the household´s financial situation; ever received money, valuables or possessions worth more than 5. 000 euros; received these financial transfers from whom; year of last gift or inheritance; household financially in arrears in the last twelve months; types of household income in the last month; household net income (in euros and categories); expected development of financial situation in the next three years. Attitudes and values: general trust in people; planning for the future; value orientation and attitudes: Traditional concept of marriage (unmarried cohabitation is okay, marriage is lifelong union, divorce is okay); traditional family (women need children for fulfilling life, men need children for fulfilling life, equal rights for homosexual couples); gender role (preschool child suffers when mother works, loving and stable mother-child relationship when mother works, women should care about family and less about career); intergenerational values (parents should financially support adult children, children should take responsibility for their parents´ care, children should financially support their parents), gender roles (better political leadership, for whom is university education more important, for whom is a job more important, for whom is household and child care more important, better care for young children); experiment on ideal employment status and ideal weekly work hours of mother and father by age of child; religious community; frequency of participation in religious events per week, month, or year; religiosity; experience of Corona pandemic (personally heavily burdened, fear of contracting COVID-19, time also had good sides, financial losses, difficulty limiting personal contacts). Demography: sex; sex according to registry data; age; date of birth (month, year); age according to registry data; migration background; currently residing in eastern Germany; degree of urbanization; current partnership status: relationship present; satisfaction with current relationship; age of partner; number of all children, number of biological children, number of adopted children, and stepchildren born before interview. Additionally coded: ID anchor; wave data collection; identifier for sample membership; interview date (day, month, year); mode of participation; terminal device; total duration of Web interview in seconds; contact strategy; incentive experiment; experimental groups work by age

Notch Signaling Mediates Differentiation in Barrett\u27s Esophagus and Promotes Progression to Adenocarcinoma

© 2020 AGA Institute Background & Aims: Studies are needed to determine the mechanism by which Barrett\u27s esophagus (BE) progresses to esophageal adenocarcinoma (EAC). Notch signaling maintains stem cells in the gastrointestinal tract and is dysregulated during carcinogenesis. We explored the relationship between Notch signaling and goblet cell maturation, a feature of BE, during EAC pathogenesis. Methods: We measured goblet cell density and levels of Notch messenger RNAs in BE tissues from 164 patients, with and without dysplasia or EAC, enrolled in a multicenter study. We analyzed the effects of conditional expression of an activated form of NOTCH2 (pL2.Lgr5.N2IC), conditional deletion of NOTCH2 (pL2.Lgr5.N2fl/fl), or loss of nuclear factor κB (NF-κB) (pL2.Lgr5.p65fl/fl), in Lgr5+ (progenitor) cells in L2-IL1B mice (which overexpress interleukin 1 beta in esophagus and squamous forestomach and are used as a model of BE). We collected esophageal and stomach tissues and performed histology, immunohistochemistry, flow cytometry, transcriptome, and real-time polymerase chain reaction analyses. Cardia and forestomach tissues from mice were cultured as organoids and incubated with inhibitors of Notch or NF-kB. Results: Progression of BE to EAC was associated with a significant reduction in goblet cell density comparing nondysplastic regions of tissues from patients; there was an inverse correlation between goblet cell density and levels of NOTCH3 and JAG2 messenger RNA. In mice, expression of the activated intracellular form of NOTCH2 in Lgr5+ cells reduced goblet-like cell maturation, increased crypt fission, and accelerated the development of tumors in the squamocolumnar junction. Mice with deletion of NOTCH2 from Lgr5+ cells had increased maturation of goblet-like cells, reduced crypt fission, and developed fewer tumors. Esophageal tissues from in pL2.Lgr5.N2IC mice had increased levels of RelA (which encodes the p65 unit of NF-κB) compared to tissues from L2-IL1B mice, and we found evidence of increased NF-κB activity in Lgr5+ cells. Esophageal tissues from pL2.Lgr5.p65fl/fl mice had lower inflammation and metaplasia scores than pL2.Lgr5.N2IC mice. In organoids derived from pL2-IL1B mice, the NF-κB inhibitor JSH-23 reduced cell survival and proliferation. Conclusions: Notch signaling contributes to activation of NF-κB and regulates differentiation of gastric cardia progenitor cells in a mouse model of BE. In human esophageal tissues, progression of BE to EAC was associated with reduced goblet cell density and increased levels of Notch expression. Strategies to block this pathway might be developed to prevent EAC in patients with BE

Data from an International Multi-Centre Study of Statistics and Mathematics Anxieties and Related Variables in University Students (the SMARVUS Dataset)

This large, international dataset contains survey responses from N = 12,570 students from 100 universities in 35 countries, collected in 21 languages. We measured anxieties (statistics, mathematics, test, trait, social interaction, performance, creativity, intolerance of uncertainty, and fear of negative evaluation), self-efficacy, persistence, and the cognitive reflection test, and collected demographics, previous mathematics grades, self-reported and official statistics grades, and statistics module details. Data reuse potential is broad, including testing links between anxieties and statistics/mathematics education factors, and examining instruments’ psychometric properties across different languages and contexts. Data and metadata are stored on the Open Science Framework website (https://osf.io/mhg94/)

Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome.

BACKGROUND: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. OBJECTIVE: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. METHODS: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. RESULTS: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. CONCLUSION: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome